title: Toxicokinetics/Toxicodynamics of γ-hydroxybutyrate-ethanol intoxication: evaluation of potential treatment strategies.
abstract: γ-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1-0.2% and 0.3-0.4% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABAA receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABAB receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1-0.2% (4 of 10) and 0.3-0.4% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, l-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1-0.2% (0 of 10) and 0.3-0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3-0.4% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABAB receptor inhibition represent potentially effective treatments in GHB-ethanol intoxication.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA.
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Morse
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics* / Q000633:toxicity*; D016292:Procedural Sedation / Q000401:mortality; D062787:Drug Overdose / Q000188:drug therapy; D000431:Ethanol / Q000493:pharmacokinetics* / Q000633:toxicity*; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D019344:Lactic Acid / Q000627:therapeutic use; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D010991:Plethysmography; D011041:Poisoning / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality; D015656:Respiratory Mechanics / Q000187:drug effects; D012978:Sodium Oxybate / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D002492:Central Nervous System Depressants; D058788:GABA-B Receptor Antagonists; D006993:Hypnotics and Sedatives; D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid; D000431:Ethanol; D012978:Sodium Oxybate